The electronic structure of diatomic nickel oxide.

The nature of the Ni-O bond is relevant to catalytic and environmental applications. The vibrational frequency and electronic structure of NiO were calculated using CASSCF, icMRCI+Q, CCSD(T), and DFT. CASSCF predicted a quintet state (5Σ-) ground state for the equilibrium bond distance with a state crossing at 1.65 Å, where the triplet (3Σ-) state becomes of lower energy. These states arise from the 3d8(3F)4s2 (3F) and 3d9(2D)4s1 (3D) configurations of Ni. The icMRCI+Q method predicts a triplet (3Σ-) ground state and does not predict a state crossing with the quintet. This state has significant ionic character with the 2pz of O bonding with the 4s/3dz2 of the Ni to form a σ bond. The NiO frequency at the icMRCI+Q level of 835.0 cm-1 is in excellent agreement with experiment; the value of re is 1.5992 Å at this computational level. CCSD(T) predicts ωe = 888.80 cm-1 when extrapolated to the complete basis set limit. Frequencies predicted using CCSD(T) deviate from experiment consistent with the calculations showing large multireference character. A wide array of density functionals were benchmarked. Of the 43 functionals tested, the ones that gave the best prediction of the frequency are ωB97XD, CAM-B3LYP, and τ-HCTH with respective values of 831.8, 838.3, and 837.4 cm-1 respectively. The bond dissociation energy (BDE) of NiO is predicted to be 352.4 kJ mol-1 at the Feller-Peterson-Dixon (FPD) level in good agreement with one of the experimental values. The calculated BDEs at the DFT level are sensitive to the choice of functional and atomic asymptote. Sixteen functionals predicted the BDE within 20 kJ mol-1 of the FPD value.

Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. OBJECTIVE: To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. METHODS: We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. RESULTS: A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. CONCLUSIONS: In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists. METHODS: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519. FINDINGS: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study. INTERPRETATION: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control. FUNDING: AstraZeneca.

Outcomes of a Fatigue Management Intervention for People With Post COVID-19 Condition.

OBJECTIVE: Fatigue is identified as one of the most prevalent and persistent problems reported by people with post COVID-19 condition that negatively impacts on everyday living and resumption of pre-COVID-19 lifestyle. A pilot occupational therapy fatigue management intervention was designed for patients presenting with post COVID-19 condition fatigue. DESIGN: A retrospective analysis was carried out after the delivery of the fatigue management intervention. Self-reported measures of fatigue, well-being, and health status were taken at baseline and repeated at 2 wks after intervention. Baseline and postintervention scores were compared using nonparametric analysis. RESULTS: Sixty participants (73% female), median age 50.5 yrs (range, 17-74), 93% reporting symptoms persisting for 12 wks or longer, completed the fatigue management intervention. All participants reported moderate to severe fatigue impacting on everyday activity at baseline. The greatest impact of fatigue was on engagement in leisure and work activity. Statistically significant improvement in fatigue ( P < 0.001), well-being ( P < 0.001), and health status ( P < 0.001) were noted after the intervention. CONCLUSIONS: Findings indicate the potential of occupational therapy fatigue management interventions to enable self-management strategies and reduce the negative impact of fatigue among people with post COVID-19 condition.

Diagnosing and managing pleural disease.

This issue of Breathe focuses on the management of pleural disease https://bit.ly/4a7dh1S.

The changing face of the modern respiratory clinician.

This issue of Breathe examines both the integral role multidisciplinary care has in managing respiratory disease, and the changing faces of the respiratory clinicians providing that care. https://bit.ly/47MsW5R.

Climate change, the environment and respiratory disease.

Respiratory clinicians are no strangers to the concept of both occupational and recreational exposures affecting the lung, but evolving factors like climate change and air quality can also play a critical role in respiratory health. https://bit.ly/42XFCUA.

Nocturnal Hypoxemia Associates With Symptom Progression and Mortality in Patients With Progressive Fibrotic Interstitial Lung Disease.

BACKGROUND: OSA and nocturnal hypoxemia (NH) are common in patients with fibrotic interstitial lung disease (F-ILD), but their relationship with disease outcomes remains unclear. RESEARCH QUESTION: What is the relationship between NH and OSA and clinical outcomes in patients with F-ILD? STUDY DESIGN AND METHODS: This was a prospective observational cohort study of patients with F-ILD and without daytime hypoxemia. Patients underwent home sleep study at baseline and were followed up for at least 1 year or until death. NH was defined as ≥ 10% of sleep with oxygen saturation of < 90%. OSA was defined as an apnea-hypopnea index of ≥ 15 events/h. RESULTS: Among 102 participants (male, 74.5%; age, 73.0 ± 8.7 years; FVC, 2.74 ± 0.78 L; 91.1% idiopathic pulmonary fibrosis), 20 patients (19.6%) demonstrated prolonged NH and 32 patients (31.4%) showed OSA. No significant differences were found between those with and without NH or OSA at baseline. Despite this, NH was associated with a more rapid decline in both quality of life as measured by the King's Brief Interstitial Lung Disease questionnaire (change, -11.3 ± 5.3 points in the NH group vs -6.7 ± 6.5 in those without NH; P = .005) and higher all-cause mortality at 1 year (hazard ratio, 8.21; 95% CI, 2.40-28.1; P < .001). No statistically significant difference was seen between the groups in annualized change in measures of pulmonary function testing. INTERPRETATION: Prolonged NH, but not OSA, is associated with worsening disease-related quality of life and increased mortality in patients with F-ILD.

Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial.

BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods. METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete. FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 µg daily to 1000 µg daily (500 µg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 µg once daily to 500 µg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA. INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden. FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.

What we do and do not know about managing respiratory disease in pregnancy.

Respiratory disorders are common in pregnant women, but their exclusion from clinical trials makes decisions around pharmacotherapy challenging. Developing programmes designed to improve evidence in pregnancy should be a priority for respiratory research. https://bit.ly/3n6aX42.

1-year quality of life and health-outcomes in patients hospitalised with COVID-19: a longitudinal cohort study.

BACKGROUND: Published studies suggest physical recovery from the COVID-19 is complex, with many individuals experiencing persistent symptoms. There is a paucity of data investigating the longer-term trajectory of physical recovery from COVID-19. METHODS: A prospective longitudinal design was utilised to investigate the impact COVID-19 has on physical functioning at 10-weeks (T1), 6-months (T2) and 1-year (T3) post-hospital discharge. Objective measures of recovery included 6-Minute Walk Test Distance (6MWTD), frailty (Clinical Frailty Scale), quantification of falls following hospital-discharge, return to work status and exercise levels. Subjective markers included symptoms (COVID-19-Specific Patient Concerns Assessment), fatigue (Chalder Fatigue Score) and health-related quality of life (HrQOL) [Short-Form-36 Health Survey Questionnaire (SF-36-II)]. Univariate analysis was performed using t-test, Wilcoxon rank-sum, and Chi-squared test, paired analysis using one-way analysis of variance and Krustal Wallis testing and correlation analysis with Spearman correlation tests. RESULTS: Sixty-one subjects participated. Assessments were conducted at a median of 55 days(T1), 242 days(T2), and 430 days(T3) following hospital-discharge. 6MWTD improved significantly overtime (F = 10.3, p < 0.001) from 365(209)m at T1 to 447(85)m at T3, however remained below population norms and with no associated improvement in perceived exertion. Approximately half (n = 27(51%)) had returned to pre-diagnosis exercise levels at T3. At least one concern/symptom was reported by 74%, 59% and 64% participants at T1, T2 and T3 respectively. Fatigue was the most frequently reported symptom at T1(40%) and T2(49%), while issues with memory/concentration was the most frequently reported at T3(49%). SF-36 scores did not change in any domain over the study period, and scores remained lower than population norms in the domains of physical functioning, energy/vitality, role limitations due to physical problems and general health. Return-to-work rates are low, with 55% of participants returning to work in some capacity, and 31% of participants don't feel back to full-health at 1-year following infection. CONCLUSION: Hospitalised COVID-19 survivors report persistent symptoms, particularly fatigue and breathlessness, low HrQOL scores, sub-optimal exercise levels and continued work absenteeism 1-year following infection, despite some objective recovery of physical functioning. Further research is warranted to explore rehabilitation goals and strategies to optimise patient outcomes during recovery from COVID-19. CLINICAL MESSAGE: Hospitalised COVID-19 survivors report significant ongoing rehabilitation concerns 1-year following infection, despite objective recovery of physical functioning. Our findings suggest those who returned to exercise within 1-year may have less fatigue and breathlessness. The impact of exercise, and other rehabilitative strategies on physical functioning outcomes following COVID-19 should be investigated in future research.

Infectious disease in respiratory medicine.

COVID-19 has brought respiratory infections into the spotlight, but other infectious diseases remain important causes of respiratory illness and death https://bit.ly/36t6Rhf.

Pulmonary vascular disease for the general respiratory clinician.

Pulmonary vascular disease is relevant to many practising respiratory clinicians: ∼1% of the world's population is estimated to have PH, and it is an important consequence of many other respiratory diseases (e.g. COPD, ILD, sleep breathing disorders) https://bit.ly/3hLqUx1.

Using Fractional Exhaled Nitric Oxide Measurement in Clinical Asthma Management.

Asthma is a common and heterogeneous disease characterized by lower airway inflammation and airflow limitation. Critical factors in asthma management include establishing an accurate diagnosis and ensuring appropriate selection and dosage of antiinflammatory therapies. Most patients with asthma exhibit type 2 inflammation, with increased IL-4, IL-5, and IL-13 signalling, often with associated eosinophilia. Identifying lower airway eosinophilia with sputum induction improves asthma outcomes, but is time-consuming and costly. Increased type 2 inflammation leads to upregulation of nitric oxide (NO) release into the airway, with increasing fractional exhaled NO (Feno) reflecting greater type 2 inflammation. Feno can be measured easily and quickly in the clinic, offering a point-of-care surrogate measurement of the degree of lower airway inflammation. Feno testing can be used to help confirm an asthma diagnosis, to guide inhaled corticosteroid therapy, to assess adherence to treatment, and to aid selection of appropriate biologic therapy. However, Feno levels also may be influenced by a variety of intrinsic and extrinsic factors other than asthma, including nasal polyposis and cigarette smoking, and must be interpreted in the broader clinical context, rather than viewed in isolation. This review discusses the clinical application of Feno measurement in asthma care, from diagnosis to treatment selection, and describes its place in current international expert guidelines.

Emergency medical admissions and COVID-19: impact on 30-day mortality and hospital length of stay.

BACKGROUND: The COVID-19 pandemic has put considerable strain on healthcare systems. AIM: To investigate the effect of the COVID-19 pandemic on 30-day in-hospital mortality, length of stay (LOS) and resource utilization in acute medical care. METHODS: We compared emergency medical admissions to a single secondary care centre during 2020 to the preceding 18 years (2002-2019). We investigated 30-day in-hospital mortality with a multiple variable logistic regression model. Utilization of procedures/services was related to LOS with zero truncated Poisson regression. RESULTS: There were 132,715 admissions in 67,185 patients over the 19-year study. There was a linear reduction in 30-day in-hospital mortality over time; over the most recent 5 years (2016-2020), there was a relative risk reduction of 36%, from 7.9 to 4.3% with a number needed to treat of 27.7. Emergency medical admissions increased 18.8% to 10,452 in 2020 with COVID-19 admissions representing 3.5%. 18.6% of COVID-19 cases required ICU admission with a median stay of 10.1 days (IQR 3.8, 16.0). COVID-19 was a significant univariate predictor of 30-day in-hospital mortality, 18.5% (95%CI: 13.9, 23.1) vs. 3.0% (95%CI: 2.7, 3.4)-OR 7.3 (95%CI: 5.3, 10.1). ICU admission was the dominant outcome predictor-OR 12.4 (95%CI: 7.7, 20.1). COVID-19 mortality in the last third of 2020 improved-OR 0.64 (95%CI: 0.47, 0.86). Hospital LOS and resource utilization were increased. CONCLUSION: A diagnosis of COVID-19 was associated with significantly increased mortality and LOS but represented only 3.5% of admissions and did not attenuate the established temporal decline in overall in-hospital mortality.

Non-dipping nocturnal blood pressure correlates with obstructive sleep apnoea severity in normotensive subjects and may reverse with therapy.

BACKGROUND: Obstructive sleep apnoea (OSA) is strongly associated with systemic hypertension, but there are limited data on the relationship with blood pressure (BP) in normotensive subjects. Here, we examined the relationship of OSA with nocturnal BP in a documented diurnal normotensive cohort, explored potential intermediate pathways and assessed the effects on BP of continuous positive airways pressure (CPAP) therapy. METHODS: 65 males referred for assessment of possible OSA and normotensive on 24-hour BP monitoring underwent overnight inpatient polysomnography (age 41±7 years, body mass index (BMI) 34±6 kg·m-2, apnoea-hypopnoea index (AHI) 14 (interquartile range 5-26)). Urine and serum were assessed for markers of sympathetic activation, renin-angiotensin-aldosterone system activity, oxidative stress, endothelial function and systemic inflammation. In a subset of patients, 24-hour BP monitoring was repeated after CPAP therapy. RESULTS: Within this normotensive cohort, night-time systolic and diastolic BP and nocturnal BP dip were highest in the fourth OSA severity quartile (p<0.05). Nocturnal BP dip correlated with AHI (r=-0.327, p<0.05) and oxygen desaturation index (ODI) (r=-0.371, p<0.05), but only ODI was an independent predictor of BP dip (B=-0.351, p<0.01) and non-dipping status (B=0.046, p<0.05). Overnight urinary norepinephrine correlated with nocturnal systolic BP (r=0.387, p<0.01) with a trend towards correlation with systolic dipping (p=0.087). In 20 CPAP-treated patients, night-time systolic BP decreased (p<0.05) and mean nocturnal BP dip increased (p≤0.05). CONCLUSION: In this normotensive cohort, OSA severity was associated with higher nocturnal BP, which improved following CPAP therapy, and intermittent hypoxia was the most important OSA-related variable in this relationship.

Sleep medicine and coronavirus disease 2019.

PURPOSE OF REVIEW: To evaluate the impact of the COVID-19 pandemic on the care of people with sleep disorders, to explore relationships between OSA and COVID-19, and to describe current knowledge of the effect of the pandemic on sleep globally. RECENT FINDINGS: COVID-19 has led to significant changes in the practice of sleep medicine, including the care of patients with OSA. An OSA diagnosis may portend a worse prognosis with COVID-19, whilst prior COVID-19 may have an impact on sleep breathing. SUMMARY: The pandemic has caused marked difficulties with access to diagnostic sleep studies and reduced capacity for CPAP initiation. Conversely, adherence to CPAP therapy may have improved, and use of remote consultations and telemonitoring has increased. An OSA diagnosis may be associated with increased risk of severe COVID-19, although any apparent relationship may be attributable to confounding factors, such as obesity and metabolic disease. Small studies have reported some increase in CPAP requirements in OSA patients following COVID-19 infection. More generally, the pandemic has been associated with a deterioration in subjective sleep quality across the population; much of this appears because of increased anxiety and stress. Finally, studies assessing putative links between COVID-19 and REM sleep issues are ongoing.